Abstract
PurposeDeficiency of adenosine deaminase 2 (DADA2) is an inherited inborn error of immunity, characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure (BMF). Tumor necrosis factor (TNF-α) blockade is the treatment of choice for the vasculopathy, but often fails to reverse refractory cytopenia. We aimed to study the outcome of hematopoietic cell transplantation (HCT) in patients with DADA2.MethodsWe conducted a retrospective study on the outcome of HCT in patients with DADA2. The primary outcome was overall survival (OS).ResultsThirty DADA2 patients from 12 countries received a total of 38 HCTs. The indications for HCT were BMF, immune cytopenia, malignancy, or immunodeficiency. Median age at HCT was 9 years (range: 2–28 years). The conditioning regimens for the final transplants were myeloablative (n = 20), reduced intensity (n = 8), or non-myeloablative (n = 2). Donors were HLA-matched related (n = 4), HLA-matched unrelated (n = 16), HLA-haploidentical (n = 2), or HLA-mismatched unrelated (n = 8). After a median follow-up of 2 years (range: 0.5–16 years), 2-year OS was 97%, and 2-year GvHD-free relapse-free survival was 73%. The hematological and immunological phenotypes resolved, and there were no new vascular events. Plasma ADA2 enzyme activity normalized in 16/17 patients tested. Six patients required more than one HCT.ConclusionHCT was an effective treatment for DADA2, successfully reversing the refractory cytopenia, as well as the vasculopathy and immunodeficiency.Clinical ImplicationsHCT is a definitive cure for DADA2 with > 95% survival.
Highlights
In 2014, biallelic deleterious mutations in the cat eye chromosome region 1 gene (CECR1, subsequently renamed ADA2), encoding adenosine deaminase 2 (ADA2), were reported as the cause of a monogenic inborn error of immunity disease, deficiency of ADA2 (DADA2) (OMIM # 615,688) [1, 2]
We invited all authors of published single case reports on hematopoietic cell transplantation (HCT) in DADA2 to participate in the study
DADA2 diagnosis was confirmed at the molecular level in all patients, by demonstrating the presence of biallelic pathogenic ADA2 variants
Summary
In 2014, biallelic deleterious mutations in the cat eye chromosome region 1 gene (CECR1, subsequently renamed ADA2), encoding adenosine deaminase 2 (ADA2), were reported as the cause of a monogenic inborn error of immunity disease, deficiency of ADA2 (DADA2) (OMIM # 615,688) [1, 2]. DADA2 diagnosis is based on an absence or low levels of plasma ADA2 enzymatic activity and the demonstration of biallelic loss-of-function mutations of ADA2 [10]. A picture emerges where ADA2 deficiency results in skewing of macrophage differentiation towards inflammatory M1 macrophages [11], leading to endothelial instability, as shown in a zebrafish model and in endothelial cell coculture systems [1]. Recent findings have revealed an even more complex interplay between endothelial cells and monocytes and macrophages with marked ADA2 secretion by endothelial cell lines [12]
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